1. Field of the Invention
The present invention is directed to novel compounds possessing both angiotensin converting enzyme inhibitory activity and neutral endopeptidase inhibitory activity and methods of preparing such compounds. The present invention is also directed to pharmaceutical compositions containing such dual inhibiting compounds or pharmaceutically acceptable salts thereof and their use in the manufacture of medicaments.
2. Description of the Art
Angiotensin-Converting Enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II is a vasoconstrictor which also stimulates aldosterone secretion by the adrenal cortex. ACE inhibition prevents both the conversion of angiotensin I to angiotensin II and the metabolism of bradykinin, resulting in decreased circulating angiotensin II, aldosterone and increased circulating bradykinin concentrations. In addition to these neurohormonal changes, decreases in peripheral resistance and blood pressure are observed, particularly in individuals with high circulating renin. Other pharmacological effects associated with ACE inhibition include regression of left ventricular hypertrophy, improvement in the clinical signs of heart failure, and reduction in mortality in patients with congestive heart failure (CHF) or left ventricular dysfunction after myocardial infarction.
Neutral endopeptidase (NEP) is an enzyme responsible for the metabolism of atrial natriuretic peptide (ANP). Inhibition of NEP results in increased ANP concentrations, which in turn leads to natriuresis, diuresis and decreases in intravascular volume, venous return and blood pressure. ANP is released by atrial myocytes in response to atrial stretch or increased intravascular volume. Elevated plasma concentrations of ANP have been demonstrated as a potential compensatory mechanism in various disease states, including congestive heart failure, renal failure, essential hypertension and cirrhosis.
The secretion of ANP by atrial myocytes causes vasodilation, diuresis, natriuresis, and the inhibition of renin release and aldosterone secretion. In contrast, angiotensin II results in vasoconstriction, sodium and water reabsorption, and aldosterone production. These two hormonal systems interact in a reciprocal or counterbalancing manner to maintain normal physiologic vascular and hemodynamic responses.
U.S. Pat. No. 5,430,145 discloses tricyclic mercaptoacetylamide derivatives useful as ACE and NEP inhibitors. The present invention relates to specific compounds covered by the generic disclosure of U.S. Pat. No. 5,430,145 which have surprisingly improved ADME (Absorption, Distribution, Metabolism, Excretion) properties over the compounds exemplified therein.
Accordingly, the present invention provides a compound of the formula I: 
wherein
R1 is hydrogen, xe2x80x94CH2OC(O)C(CH3)3, or an acyl group;
R2 is hydrogen; xe2x80x94CH2Oxe2x80x94C(O)C(CH3)3; a C1-C4-alkyl; aryl, aryl-(C1-C4-alkyl); or diphenylmethyl;
X is xe2x80x94(CH2)n wherein n is an integer 0 or 1, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, 
wherein R3 is hydrogen, a C1-C4-alkyl, aryl or aryl-(C1-C4-alkyl) and R4 is xe2x80x94CF3, C1-C10-alkyl, aryl, or aryl-(C1-C4-alkyl);
B1 and B2 are each independently hydrogen, hydroxy, or xe2x80x94OR5, wherein R5 is C1-C4-alkyl, aryl, or aryl-(C1-C4-alkyl) or, where B1 and B2 are attached to adjacent carbon atoms, B1 and B2 can be taken together with said adjacent carbon atoms to form a benzene ring or methylenedioxy.
In one embodiment, the present invention provides a compound of the formula I wherein R1 is acetyl. In another embodiment, the present invention provides a compound of the formula I wherein R1 is hydrogen. In a further embodiment, the present invention provides a compound of the formula I wherein R2 is hydrogen. In a further embodiment, the present invention provides a compound of the formula I wherein B1 and/or B2 are hydrogen. In yet a further embodiment, the present invention provides a compound of the formula I wherein X is xe2x80x94CH2.
In one embodiment, the present invention provides a compound of formula IA: 
wherein R1 is acetyl or hydrogen.
The structure of preferred embodiments according to the present invention are compounds of the formulae IB and IC below: 
The compounds of the formula I, including compounds of the formulae IA, IB and IC, are particularly useful as dual inhibitors of ACE and NEP.
The present invention accordingly provides a pharmaceutical composition comprising an effective ACE and/or NEP inhibiting amount of a compound of formula I in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.
As used herein, the term xe2x80x98C1-C4-alkylxe2x80x99 refers to a saturated straight or branched monovalent hydrocarbon chain of one, two, three or four carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, and the like groups. The term xe2x80x98C1-C10-alkylxe2x80x99 refers to a saturated straight or branched monovalent hydrocarbon chain of one to ten carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like groups.
As used herein xe2x80x98arylxe2x80x99 refers to a phenyl or naphthyl group unsubstituted or substituted with from one to three substituents selected from the group consisting of methylenedioxy, hydroxy, C1-C4-alkoxy, fluoro and chloro. Included within the scope of the term xe2x80x98aryl-(C1-C4-alkyl)xe2x80x99 are phenylmethyl (benzyl), phenylethyl, p-methoxybenzyl, p-fluorobenzyl and p-chlorobenzyl.
As used herein, xe2x80x98C1-C4-alkoxyxe2x80x99 refers to a monovalent substitutent which consists of a straight or branched alkyl chain having from 1 to 4 carbon atoms linked through an ether oxygen atom and having its free valence bond from the ether oxygen, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy and the like groups.
As used herein, xe2x80x98heterocyclexe2x80x99 means any closed-ring moiety in which one or more of the atoms of the ring are an element other than carbon and includes, but is not limited to, the following: piperidinyl, pyridinyl, isoxazolyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, benzimidazolyl, thiazolyl, thienyl, furanyl, indolyl, 1,3-benzodioxolyl, tetahydropyranyl, imidazolyl, tetrahydrothienyl, pyranyl, dioxanyl, pyrrolyl, pyrimidinyl, pyrazinyl, thiazinyl, oxazolyl, purinyl, quinolinyl and isoquinolinyl.
As used herein, xe2x80x98halogenxe2x80x99 or xe2x80x98Halxe2x80x99 refers to a member of the family of fluorine, chlorine, bromine or iodine.
As used herein, xe2x80x98acyl groupxe2x80x99 refers to aliphatic and aromatic acyl groups and those derived from heterocyclic compounds. For example, the acyl group may be a lower or (C1-C4)alkanoyl group such as formyl or acetyl, an aroyl group such as benzoyl or a heterocyclic acyl group comprising one or more of the heteroatoms O, N and S, such as the group 
As used herein, xe2x80x98stereoisomerxe2x80x99 is a general term used for all isomers of individual molecules that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
As used herein, xe2x80x98Rxe2x80x99 and xe2x80x98Sxe2x80x99 are used as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x98Rxe2x80x99 (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x98Sxe2x80x99 (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon sequence rules wherein prioritization is first based on atomic number (in order of decreasing atomic number). A listing and discussion of priorities is contained in Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Mander, editors, Wiley-Interscience, John Wiley and Sons, Inc., New York, 1994.
In addition to the (R)-(S) system, the older D-L system may also be used herein to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix xe2x80x98Dxe2x80x99 is used to represent the absolute configuration of the isomer in which the functional (determing) group is on the right side of the carbon at the chiral center and xe2x80x98Lxe2x80x99, that of the isomer in which it is on the left.
As used herein, xe2x80x98treatxe2x80x99 or xe2x80x98treatingxe2x80x99 means any treatment, including but not limited to, alleviating symptoms, eliminating the causation of the symptoms either on a temporary or permanent basis, or to preventing or slowing the appearance of symptoms and progression of the named disease, disorder or condition.
As described herein, the term xe2x80x98patientxe2x80x99 refers to a warm blooded animal such as a mammal which is afflicted with a particular disease, disorder or condition. It is explicitly understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals within the scope of the meaning of the term.
As used herein, the term xe2x80x98pharmaceutically acceptable saltxe2x80x99 is intended to apply to any salt, whether previously known or future discovered, that is used by one skilled in the art that is a non-toxic organic or inorganic addition salt which is suitable for use as a pharmaceutical. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium or magnesium hydroxides; ammonia and aliphatic, cyclic or aromatic amines such as methylamine, dimethylamine, triethylamine, diethylamine, isopropyidiethylamine, pyridine and picoline. Illustrative acids which form suitable salts include inorganic acids such as, for example, hydrochloric, hydrobromic, sulfuric, phosphoric and like acids, and organic carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, mandelic and like acids, and organic sulfonic acids such as methanesulfonic and p-toluenesulfonic acids.
As used herein, xe2x80x98pharmaceutical carrierxe2x80x99 refers to known pharmaceutical excipients useful in formulating pharmaceutically active compounds for administration, and which are substantially nontoxic and nonsensitizing under conditions of use. The exact proportion of these excipients is determined by the solubility and chemical properties of the active compound, the chosen route of administration as well as standard pharmaceutical practice.
Compounds according to the present invention may be prepared as follows.
The tricyclic moiety of the compounds of the formula I may be prepared utilizing procedures and techniques well known and appreciated by one of ordinary skill in the art. U.S. Pat. No. 5,430,145 describes examples of suitable procedures and the content of this document is incorporated herein by reference. One such procedure, as illustrated in Scheme A, is described below: 
In step a, the appropriate phthalimide blocked (S)-phenylalanine derivative of structure 2 can be prepared by reacting the appropriate (S)-phenylalanine derivative of structure 1 with phthalic anhydride in a suitable aprotic solvent, such as dimethylformamide.
In step b, the appropriate phthalimide blocked (S)-phenylalanine derivative of structure 2 can be converted to the corresponding acid chloride, then reacted with the appropriate amino acid methyl ester of structure 3 in a coupling reaction. For example, the appropriate phthalimide blocked (S)-phenylalanine derivative of structure 2 can be reacted with oxalyl chloride in a suitable aprotic solvent, such as methylene chloride. The resulting acid chloride can then be coupled with the appropriate amino acid methyl ester of structure 3 using a suitable base, such as N-methylmorpholine in a suitable aprotic solvent, such as dimethylformamide, to give the appropriate 1-oxo-3-phenylpropyl-amino acid methyl ester derivative of structure 4.
In step c, the hydroxymethylene functionality of the appropriate 1-oxo-3-phenylpropyl-amino acid methyl ester derivative of structure 4 can be oxidized to the appropriate aldehyde of structure 5 by oxidation techniques well known and appreciated in the art. For example, the hydroxymethylene functionality of the appropriate 1-oxo-3-phenylpropyl-amino acid methyl ester derivative of structure 4 can be oxidized to the appropriate aldehyde of structure 5 by means of a Swern oxidation using oxalyl chloride and dimethylsulfoxide in a suitable aprotic solvent, such as methylene chloride.
In step d, the appropriate aldehyde of structure 5 can be cyclized to the appropriate enamine of structure 6 by acid catalysis. For example, the appropriate aldehyde of structure 5 can be cyclized to the appropriate enamine of structure 6 by treatment with trifluoroacetic acid in a suitable aprotic solvent, such as methylene chloride.
In step e, the appropriate enamine of structure 6 can be converted to the corresponding tricyclic compound of structure 7 by an acid catalyzed Friedel-Crafts reaction. For example, the appropriate enamine of structure 6 can be converted to the corresponding tricyclic compound of structure 7 by treatment with a mixture of trifluoromethane sulfonic acid and trifluoroacetic anhydride in a suitable aprotic solvent, such as methylene chloride.
In step e, it may be necessary to reesterify the carboxy functionality due to the conditions of the work-up. For example, treatment of the crude product with bromodiphenylmethane in a suitable aprotic solvent, such as dimethyl-formamide along with a non-nucleophilic base, such as cesium carbonate, may be used to give the corresponding diphenylmethyl ester.
In step f, the phthalimide protecting group of the appropriate tricyclic compound of structure 7 can be removed using techniques and procedures well known in the art. For example, the phthalimide protecting group of the appropriate tricyclic compound of structure 7 can be removed using hydrazine monohydrate in a suitable protic solvent such as methanol, to give the corresponding amino compound of structure 8.
In step g, the appropriate (S)-acetate compound of structure 10 can be prepared by reacting the appropriate amino compound of structure 8 with the appropriate (S)-acetate of structure 9. For example, the appropriate amino compound of structure 8 can be reacted with the appropriate (S)-acetate compound of structure 9 in the presence of a coupling reagent such as EEDQ (1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), or diethylcyanophosponate in a suitable aprotic solvent, such as methylene chloride to give the appropriate (S)-acetoxy compound of structure 10.
In step h, the (S)-acetate functionality of the appropriate amide compound of structure 10 can be hydrolyzed to the corresponding (S)-alcohol of structure 11a with a base, such as lithium hydroxide in a suitable solvent mixture, such as tetrahydrofuran and ethanol.
In step i, the (S)-alcohol functionality of the appropriate amide compound of structure 11a can be converted to the corresponding (R)-thioacetate or (R)-thiobenzoate of structure 12a. For example, the appropriate (S)-alcohol of structure 11a can be treated with thiolacetic acid in a Mitsunobu reaction using triphenylphosphine and DIAD (diisopropylazodicarboxylate) in a suitable aprotic solvent, such as tetrahydrofuran.
In step j, the (S)-alcohol functionality of the appropriate amide compound of structure 11a can be converted to the corresponding (R)-alcohol of structure 11b. For example, the appropriate (S)-alcohol of structure 11a can be treated with acetic acid in a Mitsunobu reaction using triphenylphosphine and DIAD in a suitable aprotic solvent, such as tetrahydrofuran. The resulting (R)-acetate can then be hydrolyzed with a suitable base, such as lithium hydroxide.
In step k, the (R)-alcohol functionality of the appropriate amide compound of structure 11b can be converted to the corresponding (S)-thioacetate or (S)-thiobenzoate of structure 12b. For example, the appropriate (R)-alcohol of structure 11b can be treated with thiolacetic acid in a Mitsunobu reaction using triphenylphosphine and DIAD in a suitable aprotic solvent, such as tetrahydrofuran.
As summarized in Table 1, the R1 and R2 groups on the compounds of structures 12a and 12b can be manipulated using techniques and procedures well known and appreciated by one of ordinary skill in the art to give the corresponding compounds of structures 13a-14a and 13b-14b.
For example, the diphenylmethyl ester functionality of the appropriate compound of structure 12a can be removed using trifluoroacetic acid to give the appropriate carboxylic acid compound of structure 13a. Similarly, the diphenylmethyl ester functionality of the appropriate compound of structure 12b can be removed using trifluoroacetic acid to give the carboxylic acid compound of structure 13b.
The (R)-thioacetate or (R)-thiobenzoate functionality of the appropriate compound of structure 13a can be removed with lithium hydroxide in a suitable solvent mixture such as tetrahydrofuran and ethanol to give the appropriate (R)-thio compound of structure 14a. Similarly, the (S)-thioacetate or (S)-thiobenzoate functionality of the appropriate compound of structure 13b can be removed with lithium hydroxide in a suitable solvent mixture such as tetrahydrofuran and ethanol to give the appropriate (S)-thio compound of structure 14b.
Although the general procedures outlined in Scheme A show the preparation of the compounds of the formula I wherein the group xe2x80x94COOR2 is of the (S)-configuration, the compounds of the formula I wherein the group xe2x80x94COOR2 is of the (R)-configuration may be prepared by analogous procedures by substituting an appropriate (R)-amino acid methyl ester for the (S)-amino acid methyl ester of structure 3 in step b.
Starting materials for use in the general synthetic procedures outlined in Scheme A are readily available to one of ordinary skill in the art. For example, certain (R)- and (S)-carboxy acetate or benzoate starting materials of structure 9 can be prepared by stereoselective reduction of the corresponding pyruvate compounds with alpine boranes as described in J. Org. Chem. 47, 1606 (1982), J. Org. Chem. 49, 1316 (1984), and J. Am. Chem. Soc. 106, 1531 (1984), followed by treating the resulting alcohol with acetic anhydride or benzoic anhydride to give the corresponding (R)- or (S)-carboxy acetate or benzoate compounds of structure 9.
Alternatively, certain tricyclic compounds of structure 7 may be prepared as described in European patent application EP 249223 A.
The present invention provides a process for the preparation of a compound of the formula I above, comprising
reacting a compound of the formula II 
where R2, X, B1 and B2 are as previously defined and Hal is halogen,
with a compound of the formula R1SH, where R1 is as previously defined, in the presence of a base, such as an alkali metal carbonate.
The present invention furthermore provides a process for the preparation of a compound of the formula II, comprising reacting a compound of the formula III 
wherein R2, X, B1 and B2 are as previously defined with a compound of the formula IV 
where Hal is halogen.
An alternative process for the preparation of a compound of the formula I according to the present invention comprises reacting a compound of the formula III 
wherein R2, X, B1 and B2 are as previously defined, with a compound of the formula V 
wherein R1 is as previously defined.
In the latter process, the appropriate amino compound of the formula III may be reacted with the appropriate (S)- or (R)-thioacetate of the formula V to give the corresponding (S)- or (R)-thioacetate, respectively, of the formula I as described previously in Scheme A, step g.
Scheme B provides another general synthetic procedure for preparing compounds of the formula I. 
In step a, the appropriate amino compound of structure 28 wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 is reacted with the appropriate (R)-bromoacid of structure 33 to give the corresponding (R)-bromoamide compound of structure 34 wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 under similar conditions as described previously in Scheme A, step g.
Alternatively, the appropriate amino compound of structure 28 wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 is reacted with the appropriate (S)-bromoacid to give the corresponding (S)-bromoamide wherein X is O, S, NH or (CH2)n wherein n is 0 or 1, or the appropriate amino compound of structure 28 wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 is reacted with the appropriate enantiomeric mixture of the bromoacid to give the corresponding diastereoisomeric mixture of the bromoamide wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 as described previously in Scheme A, step g.
In step b, the (R)-bromo functionality of the appropriate (R)-bromoamide compound of structure 34 wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 is converted to the corresponding (S)-thioacetate or (S)-thiobenzoate of structure 36, wherein X is O, S, NH or (CH2)n wherein n is 0 or 1.
Alternatively, the (S)-bromo functionality of the appropriate (S)-bromoamide wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 is converted to the corresponding (R)-thioacetate or (R)-thiobenzoate wherein X is O, S, NH or (CH2)n wherein n is 0 or 1.
For example, the appropriate (R)-bromoamide compound of structure 34 wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 is reacted with thiolacetic acid or thiolbenzoic acid of structure 35 in the presence of a base, such as cesium or sodium carbonate. The reactants are typically contacted in a suitable organic solvent such as a mixture of dimethylformamide and tetrahydrofuran. The reactants are typically stirred together at room temperature for a period of time ranging from 1 to 8 hours. The resulting (S)-thioacetate or (S)-thiobenzoate of structure 36 wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by chromatography.
Alternatively, the bromo functionality of the appropriate diastereoisomeric mixture of the bromoamides described supra wherein X is O, S, NH or (CH2)n wherein n is 0 or 1 is converted to the corresponding diastereoisomeric mixture of thioacetate or thiobenzoate compounds wherein X is O, S, NH or (CH2)n wherein n is 0 or 1.
Although Scheme B provides for the preparation of compounds of formula I wherein the tricyclic moiety has a 4-carboxy functionality of the (S)-configuration when for example X is xe2x80x94CH2, the compounds of formula I wherein the carboxy functionality is of the (R)-configuration may be prepared by substituting the appropriate (4R)-carboxy amino compound for the amino compound of structure 28 whose preparation is described in Scheme A.
The following Examples present typical syntheses as described in Scheme B. These Examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: xe2x80x98gxe2x80x99 refers to grams; xe2x80x98mmolxe2x80x99 refers to millimoles; xe2x80x98mlxe2x80x99 refers to milliliters; xe2x80x98xc2x0 C.xe2x80x99 refers to degrees Celsius.